Systemic Treatment of Advanced Hepatocellular Carcinoma in Older Adults
Luisa M. Arellano and Sukeshi Patel Arora*
Mays Cancer Center, UT Health Science Center San Antonio, 7979 Wurzbach Rd, MC 8026, San Antonio, TX 78229, USA
Over the past 30 years, the incidence in of hepatocellular carcinoma (HCC) in the United States has tripled, largely due to untreated chronic Hepatitis C virus, alcoholic hepatitis, and non-alcoholic steatohepatitis (NASH). Additionally, the incidence of HCC among South Texas Hispanics is higher than elsewhere in the United States. The median age of HCC is 62 years in United States and 67 years in South Texas, with over 30% being 70 years of age or older. However, there is limited data on how to treat older adults with advanced HCC. In this review, we will discuss treatment options for older adults with advanced HCC, further emphasizing the need for prospective studies in this population.
hepatocellular carcinoma | older adult | treatment options | targeted therapy | sorafenib
Hepatocellular carcinoma (HCC) is the sixth most common cancer globally and is the third leading cause of cancer deaths. Over 700,000 new cases of HCC are diagnosed each year worldwide with large geographic variation in both risk factors and incidence (1, 2). With an overall 5-year survival of <12%, HCC has become the fastest rising cause of cancer related death in the U.S. (2). Despite the decrease of incidence in the East, the incidence of HCC in the U.S. has tripled in the last 30 years. The incidence rates of HCC in Texas has increased 69% in the last decade and are 2.6 times higher in Hispanics compared with non-Hispanic whites (2-4). This is largely because of chronic Hepatitis C Virus (HCV), alcoholic liver disease, and non-alcoholic steatohepatitis (NASH) (2-4). Additionally, the incidence of HCC among South Texas Hispanics is higher than elsewhere in the U.S., which may be associated with greater prevalence of obesity and diabetes (4). The median age of HCC is 62 years in U.S. and 67 years in South Texas, with over 30% in patients 70+ years of age (4). With an increased longevity of the population, the number of older patients with HCC is expected to increase. HCC in the U.S. is a unique disease from the East, but most studies are based on non-U.S. patients. Therefore, more studies are needed to evaluate the biology of HCC in the U.S. population.
Characteristics of HCC in older adults
Retrospective analyses from international studies show mixed data on clinical and disease characteristics of HCC in older patients. Retrospective data, predominantly from non-U.S. patients show that older patients have similar stages, survival and toxicity (5-7). However, they have less liver fibrosis, receive less curative treatment, and have more HCV, NASH, and comorbidities as compared to younger patients (5-7). Therefore, prospective characterization of the unique biology of HCC in older U.S. adults would allow us to treat these patients with a personalized approach.
Treatment of HCC in older adults
Treatment patterns in older HCC patients would allow us to identify barriers to treatment and risk factors for increased morbidity in older patients. Due to the lack of assessments utilized to identify patients at higher risk of toxicity, treatment patterns vary among providers, with some older patients overtreated and others undertreated. Although fit older adults were represented in these global studies, patients who have vulnerability or frailty, organ dysfunction and comorbidities were excluded due to strict inclusion criteria. Therefore, applying results of large phase III clinical trials to older patients who are vulnerable or frail can result in increased morbidity and mortality.
Treatment of HCC in all older patients based on clinical trials of young patients and fit older adults without comorbidities may be inappropriate. For HCC confined to the liver, available treatment options include surgery, ablative therapies, such as radiofrequency ablation (RFA), or transarterial chemoem-bolization (TACE), all of which achieve modest response (2). Up to 80% of patients initially presenting with HCC have advanced unresectable or metastatic disease. Systemic therapy is the only option for patients with advanced metastatic disease. Currently, there are several treatment options for HCC, including multi-kinase inhibitors such as first-line agent sorafenib, second-line agent regorafenib, and immunotherapy agent nivolumab.
Sorafenib, a multi-kinase inhibitor of Raf/MEK/ERK signaling and the receptor tyrosine kinase, was shown to induce apoptosis and inhibit tumor proliferation as well as angiogenesis in a variety of tumors (8). The molecular involvement of the Raf-1 and tyrosine kinase signaling pathways has been well established in the pathogenesis of HCC and provides a rationale for the investigation of sorafenib in HCC treatment (9). Sorafenib is the first drug to demonstrate efficacy in HCC in a recent randomized, placebo-controlled study (SHARP), with mTTP improved from 2.8 months with placebo to 5.5 months with sorafenib, and median overall survival (mOS) improved from 7.9 months with placebo to 10.7 months with sorafenib (10).
In the SHARP trial, the mean age was 64.9 ± 11.2 years, whereas the Asia-Pacific trial mean was 51 years (range 23-86) (10). The eligibility criteria also included an Eastern Cooperative Oncology Group (ECOG) performance status score of 2 or less, Child-Pugh liver function class A, and adequate bone marrow, liver and renal function. Therefore, this study included fit older patients, yet in clinical practice, sorafenib treatment is given to vulnerable or frail patients, without knowing the true impact on treatment morbidity and mortality.
Retrospective analysis of advanced HCC patients receiving sorafenib from 2008-2013 at our institution showed mOS for <65 was 10.2 months vs 13.5 months for 65+, but not statistically significant, with no differences in mOS with dose reductions. In this cohort, 40% of patients <65 have Child-Pugh A cirrhosis versus 70% of patients 65+ have Child-Pugh A cirrhosis. Among 109 patients dose reductions in <65 vs 65+ were 64.6 vs 70% (P=0.66); survival difference were not statistically significant. We noted a trend to improved survival in 65+ patients with AST/Platelet Ratio (APRI) </=1.68, but not statistically significant. Sorafenib was tolerated in the older. Our analysis of older patients with advanced HCC showed similar mortality and toxicity to sorafenib (7, 11); but, this study was limited by its retrospective nature and lack of comprehensive geriatric assessment (CGA). The ideal candidate for sorafenib is the older adult with optimum liver function, good performance status and no co-morbidities; however, close monitoring should always be maintained (12).
In the last year, four new systemic therapies have been approved for HCC. Newer treatments, such as tyrosine kinase inhibitors, regorafenib and cabozantinib, have been approved for second-line treatment (13, 14). Most recently, lenvatinib has been approved for first-line based on a non-inferiority study in comparison to sorafenib (15). In the subgroup analysis, these studies showed that patients 65 or older received survival benefit of the new agent; however, toxicity data specific to older adults in this study have not yet been reported (13-15). Also, immunotherapy has shown to be efficacious in HCC as well. Nivolumab has been approved in HCC as a second-line treatment (16). In the CheckMate 040 study, 42% of patients were 65 or older in the escalation phase, and 47% of patients were 65 or older in the expansion phase, but the effect on toxicity and functional status is unknown in these fit older HCC patients (16). Future studies are needed to prospectively characterize the distinct disease and treatment patterns of older HCC patients as compared to younger patients.
Geriatric assessments in older adults with HCC
Geriatric assessments rather than clinical judgement should guide treatment in older patients with HCC. In addition to severity of cirrhosis, stage of HCC, and performance status (i.e., ECOG), clinical judgement has a predominant impact on the decision to treat and the type of treatments to give to older patients with HCC. Geriatric assessments have not been incorporated into the treatment algorithm for older HCC patients. As a result, the morbidity and mortality of HCC treatments is unknown in vulnerable and frail older adults. However, studies show that geriatric assessments do have significant impact on treatment decisions in older cancer patients and should be included in initial assessments (17).
CGA predicts survival and toxicity in older patients and would identify patients at-risk for increased toxicity from HCC treatments. Studies have shown that CGA is an effective method to identify older patients who benefit from treatment (18). Tools such as CARG chemotherapy tool (19) and CRASH score (20), have been validated in multiple studies to predict chemotherapy toxicity, Patients with HCC have not been studied with these tools, so it is unclear how to apply them to this particular population. Therefore, CGA should be evaluated prospectively in older HCC patients so we can identify patients who benefit from HCC treatments. We need to expand our baseline assessments to incorporate CGA to proactively address geriatric syndromes early in our treatment algorithm (Table 1).
Table 1. CGA measures to consider in older adults with HCC.
Molecular aging in HCC
The impact of systemic treatments on molecular aging in HCC patients has not been defined. Chronologic aging has been associated with an increase in senescent cell populations throughout the body (21). Most senescent cells appear to express p16Ink4a, a cyclin-dependent kinase inhibitor and tumor suppressor, and is known to increase with aging in pre-clinical and clinical models, including cancer patients (22-24). The causal relationship between cellular senescence and aging is not completely understood. It is thought that pro-inflammatory factor produced by senescent cells (IL-1, IL-6, IL-8, TNF-alpha, MCP1, MMP3), known as the SASP, mediate the aging phenotype (25). Chemotherapy is known to induce cellular senescence (24). Senescent cells, expressing p16Ink4a and senescence-associated secretory phenotype (SASP), also contribute to chemo-resistance (26). To date, these biomarkers have not been evaluated in HCC patients receiving sorafenib or other systemic treatments. Therefore, biomarkers of aging should be explored prospectively to determine if cellular senescence is associated with treatment outcomes. Further studies should explore the association of biomarkers of aging to treatment outcomes in HCC patients.
Although there is limited research indicating effective and safe treatment with tyrosine-kinase inhibitors and immunotherapy in older adults with HCC, there needs to be further research within the United States as this is a unique HCC population. Prospectively studying treatments in older adults with the incorporation of CGA are necessary so we can further individualize treatment in older adults with advanced HCC.
NCI P30 CA054174
1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. International journal of cancer Journal international du cancer. 2010;127(12):2893-917. doi: 10.1002/ijc.25516. PubMed PMID: 21351269.
2. El-Serag HB. Hepatocellular carcinoma. The New England journal of medicine. 2011;365(12):1118-27. doi: 10.1056/NEJMra1001683. PubMed PMID: 21992124.
3. Altekruse SF, McGlynn KA, Reichman ME. Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2009;27(9):1485-91. doi: 10.1200/JCO.2008.20.7753. PubMed PMID: 19224838; PMCID: 2668555.
4. Ramirez AG, Weiss NS, Holden AE, Suarez L, Cooper SP, Munoz E, Naylor SL. Incidence and risk factors for hepatocellular carcinoma in Texas Latinos: implications for prevention research. PloS one. 2012;7(4):e35573. Epub 2012/04/25. doi: 10.1371/journal.pone.0035573. PubMed PMID: 22530052; PMCID: 3329468.
5. Guo H, Wu T, Lu Q, Dong J, Ren YF, Nan KJ, Lv Y, Zhang XF. Hepatocellular carcinoma in elderly: Clinical characteristics, treatments and outcomes compared with younger adults. PloS one. 2017;12(9):e0184160. doi: 10.1371/journal.pone.0184160. PubMed PMID: 28886106; PMCID: PMC5590882.
6. Brunot A, Le Sourd S, Pracht M, Edeline J. Hepatocellular carcinoma in elderly patients: challenges and solutions. J Hepatocell Carcinoma. 2016;3:9-18. doi: 10.2147/JHC.S101448. PubMed PMID: 27574587; PMCID: PMC4994800.
7. Al-Rajabi R, Patel S, Ketchum NS, Jaime NA, Lu TW, Pollock BH, Mahalingam D. Comparative dosing and efficacy of sorafenib in hepatocellular cancer patients with varying liver dysfunction. J Gastrointest Oncol. 2015;6(3):259-67. doi: 10.3978/j.issn.2078-6891.2015.005. PubMed PMID: 26029452; PMCID: PMC4397242.
8. Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M, Cao Y, Shujath J, Gawlak S, Eveleigh D, Rowley B, Liu L, Adnane L, Lynch M, Auclair D, Taylor I, Gedrich R, Voznesensky A, Riedl B, Post LE, Bollag G, Trail PA. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer research. 2004;64(19):7099-109. doi: 10.1158/0008-5472.CAN-04-1443. PubMed PMID: 15466206.
9. Ito Y, Sasaki Y, Horimoto M, Wada S, Tanaka Y, Kasahara A, Ueki T, Hirano T, Yamamoto H, Fujimoto J, Okamoto E, Hayashi N, Hori M. Activation of mitogen-activated protein kinases/extracellular signal-regulated kinases in human hepatocellular carcinoma. Hepatology. 1998;27(4):951-8. doi: 10.1002/hep.510270409. PubMed PMID: 9537433.
10. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Haussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J, Group SIS. Sorafenib in advanced hepatocellular carcinoma. The New England journal of medicine. 2008;359(4):378-90. doi: 10.1056/NEJMoa0708857. PubMed PMID: 18650514.
11. Patel SR, Al-Rajabi RMdT, Ketchum N, Lu T-W, Pollock BH, Michalek J, Mahalingam D. Comparative efficacy of sorafenib dose in patients with advanced hepatocellular carcinoma (HCC) with varying liver dysfunction. Journal of Clinical Oncology. 2015;33(3_suppl):369-. doi: 10.1200/jco.2015.33.3_suppl.369.
12. Wong H, Tang YF, Yao TJ, Chiu J, Leung R, Chan P, Cheung TT, Chan AC, Pang RW, Poon R, Fan ST, Yau T. The outcomes and safety of single-agent sorafenib in the treatment of elderly patients with advanced hepatocellular carcinoma (HCC). Oncologist. 2011;16(12):1721-8. doi: 10.1634/theoncologist.2011-0192. PubMed PMID: 22135121; PMCID: PMC3248771.
13. Bruix J, Qin S, Merle P, Granito A, Huang Y-H, Bodoky G, Pracht M, Yokosuka O, Rosmorduc O, Breder V, Gerolami R, Masi G, Ross PJ, Song T, Bronowicki J-P, Ollivier-Hourmand I, Kudo M, Cheng A-L, Llovet JM, Finn RS, LeBerre M-A, Baumhauer A, Meinhardt G, Han G. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet.389(10064):56-66. doi: 10.1016/S0140-6736(16)32453-9.
14. Abou-Alfa GK, Meyer T, Cheng AL, El-Khoueiry AB, Rimassa L, Ryoo BY, Cicin I, Merle P, Chen Y, Park JW, Blanc JF, Bolondi L, Klumpen HJ, Chan SL, Zagonel V, Pressiani T, Ryu MH, Venook AP, Hessel C, Borgman-Hagey AE, Schwab G, Kelley RK. Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma. The New England journal of medicine. 2018;379(1):54-63. doi: 10.1056/NEJMoa1717002. PubMed PMID: 29972759.
15. Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, Baron A, Park JW, Han G, Jassem J, Blanc JF, Vogel A, Komov D, Evans TRJ, Lopez C, Dutcus C, Guo M, Saito K, Kraljevic S, Tamai T, Ren M, Cheng AL. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391(10126):1163-73. doi: 10.1016/S0140-6736(18)30207-1. PubMed PMID: 29433850.
16. El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, Kim T-Y, Choo S-P, Trojan J, Welling TH, 3rd, Meyer T, Kang Y-K, Yeo W, Chopra A, Anderson J, dela Cruz C, Lang L, Neely J, Tang H, Dastani HB, Melero I. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. The Lancet.389(10088):2492-502. doi: 10.1016/S0140-6736(17)31046-2.
17. Hamaker ME, Schiphorst AH, ten Bokkel Huinink D, Schaar C, van Munster BC. The effect of a geriatric evaluation on treatment decisions for older cancer patients--a systematic review. Acta Oncol. 2014;53(3):289-96. doi: 10.3109/0284186X.2013.840741. PubMed PMID: 24134505.
18. Tucci A, Ferrari S, Bottelli C, Borlenghi E, Drera M, Rossi G. A comprehensive geriatric assessment is more effective than clinical judgment to identify elderly diffuse large cell lymphoma patients who benefit from aggressive therapy. Cancer. 2009;115(19):4547-53. doi: 10.1002/cncr.24490. PubMed PMID: 19562776.
19. Hurria A, Mohile S, Gajra A, Klepin H, Muss H, Chapman A, Feng T, Smith D, Sun CL, De Glas N, Cohen HJ, Katheria V, Doan C, Zavala L, Levi A, Akiba C, Tew WP. Validation of a Prediction Tool for Chemotherapy Toxicity in Older Adults With Cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2016;34(20):2366-71. doi: 10.1200/JCO.2015.65.4327. PubMed PMID: 27185838.
20. Extermann M, Boler I, Reich RR, Lyman GH, Brown RH, DeFelice J, Levine RM, Lubiner ET, Reyes P, Schreiber FJ, 3rd, Balducci L. Predicting the risk of chemotherapy toxicity in older patients: the Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) score. Cancer. 2012;118(13):3377-86. doi: 10.1002/cncr.26646. PubMed PMID: 22072065.
21. Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, Kirkland JL, van Deursen JM. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature. 2011;479(7372):232-6. doi: 10.1038/nature10600. PubMed PMID: 22048312; PMCID: 3468323.
22. Kim WY, Sharpless NE. The regulation of INK4/ARF in cancer and aging. Cell. 2006;127(2):265-75. doi: 10.1016/j.cell.2006.10.003. PubMed PMID: 17055429.
23. Krishnamurthy J, Torrice C, Ramsey MR, Kovalev GI, Al-Regaiey K, Su L, Sharpless NE. Ink4a/Arf expression is a biomarker of aging. The Journal of clinical investigation. 2004;114(9):1299-307. doi: 10.1172/JCI22475. PubMed PMID: 15520862; PMCID: 524230.
24. Sanoff HK, Deal AM, Krishnamurthy J, Torrice C, Dillon P, Sorrentino J, Ibrahim JG, Jolly TA, Williams G, Carey LA, Drobish A, Gordon BB, Alston S, Hurria A, Kleinhans K, Rudolph KL, Sharpless NE, Muss HB. Effect of cytotoxic chemotherapy on markers of molecular age in patients with breast cancer. J Natl Cancer Inst. 2014;106(4):dju057. doi: 10.1093/jnci/dju057. PubMed PMID: 24681605; PMCID: PMC3982894.
25. Tchkonia T, Zhu Y, van Deursen J, Campisi J, Kirkland JL. Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. The Journal of clinical investigation. 2013;123(3):966-72. doi: 10.1172/JCI64098. PubMed PMID: 23454759; PMCID: 3582125.
26. Bhatia-Dey N, Kanherkar RR, Stair SE, Makarev EO, Csoka AB. Cellular Senescence as the Causal Nexus of Aging. Front Genet. 2016;7:13. doi: 10.3389/fgene.2016.00013. PubMed PMID: 26904101; PMCID: PMC4751276.
27. Vellas B, Villars H, Abellan G, Soto ME, Rolland Y, Guigoz Y, Morley JE, Chumlea W, Salva A, Rubenstein LZ, Garry P. Overview of the MNA--Its history and challenges. J Nutr Health Aging. 2006;10(6):456-63; discussion 63-5. PubMed PMID: 17183418.
Conflict of Interest: No conflicts declared.
* Corresponding Author. Sukeshi Patel Arora, MD, Assistant Professor, Leader in Gastrointestinal Malignancies,
Mays Cancer Center, UT Health Science Center San Antonio,
7979 Wurzbach Rd, MC 8026, San Antonio, TX 78229, USA.
Telephone: 1-210-450-1015; fax: 1-210-450-1606
© 2018 by the Journal of Nature and Science (JNSCI).